DETAILED ACTION
Status of Claims
Receipt is acknowledged of the Applicants’ Amendments and Remarks, filed March 25, 2026 which have been entered on the record.
Claims 1-2, 14, 45, 59, 64, 74, 82-84, 87, 90-91, 102, 106, and 118 and 120 are pending.
Claims 3-13, 15-44, 46-58, 60-63, 65-73, 75-81, 85-86, 88-89, 92-101, 103-105, 107-117 and 119 are/were cancelled by Applicant.
Claims 1-2, 14, 45, 59, 64, 74, 83-84, 87, and 102 are/were amended by Applicant.
Claims 87, 90-91, 102, 106, and 118 and 120 are/remain withdrawn as detailed in the Office Action dated December 31, 2024 and described in the Election/Restriction section below.
Claims 1-2, 14, 45, 59, 64, 74, and 82-84 are pending and remain under examination.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on September 8, 2025 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-2, 14, 35, 37, 45, 53, 55, 59, 64, 67, 74, and 82-84 drawn to a compound and composition of Formula (I), in the reply filed on November 22, 2024 is acknowledged.
Presently, claims 35, 37, 53, 55, and 67 are/were cancelled by Applicant.
Applicant’s election of species without traverse from claim 60, drawn to the compound SB1-G-185 shown below is also acknowledged. Compound SB1-G-185 can be found on page 200 of Applicant’s specification (first compound listed, shown below).
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Previously, Applicant introduced new claims 116-117 and cancelled claims 46 and 67.
Claims 116-117 were drawn to a compound and composition of Formula (I), which read on Group I; however, did not read on elected species SB1-G-185, and were therefore withdrawn.
Compound SB1-G-185 recites a D of formula (IA).
Claims 116-117 were drawn towards where D is of formula (IB), and the formula shown below, which did not read on the elected species.
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Presently, claims 116-117 are cancelled by Applicant, and new claims 118-120 are introduced.
Claim 118-120 recite wherein D is of the following formulas respectively, which also do not read on the elected species and are therefore withdrawn.
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As per MPEP 803.02, III: “Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability. Note that where a claim reads on multiple species, only one species needs to be taught or suggested by the prior art in order for the claim to be anticipated or rendered obvious. See, e.g., Fresenius USA, Inc. v. Baxter Int’l, Inc., 582 F.3d 1288, 1298, 92 USPQ2d 1163, 1171 (Fed. Cir. 2009)(the entire element is disclosed by the prior art if one alternative in the Markush group is in the prior art).”
“If the examiner determines that the elected species is allowable over the prior art, the examination of the Markush claim will be extended. If prior art is then found that anticipates or renders obvious the Markush claim with respect to a nonelected species, the Markush claim shall be rejected; claims to the nonelected species would still be held withdrawn from further consideration. The prior art search will not be extended unnecessarily to cover all nonelected species, and need not be extended beyond a proper Markush grouping.”
Once more, Applicant is reminded that the elected species has not been found to be allowable over the prior art; however, the search has been expanded for the targeting ligand for the purposes of compact prosecution.
The examiner additionally notes that claim 119 is canceled by Applicant.
Claims 87, 90-91, 102, 106, and 118 and 120 are/remain withdrawn from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a non-elected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 30, 2024.
Claims 1-2, 14, 45, 59, 64, 74, and 82-84 remain under examination and are the subject of this office action.
Priority
This application is a 371 National Phase Application of PCT/US2020/039304 filed June 24, 2020 that claims benefit to US provisional applications 62865780 filed June 24, 2019.
Information Disclosure Statement
One additional information disclosure statements (IDS) submitted on March 25, 2026 is acknowledged. The submission is in compliance with the provisions of 37
CFR 1.97. Accordingly, the information disclosure statement is being considered by the
examiner.
Response to Amendment
The Declaration under 37 CFR 1.132 filed March 25, 2026 is insufficient to overcome the rejection of claim 1-2, 14, 45, 59, 64, 74, and 82-84 as set forth in the last Office action because: the declaration simply establishes that SK-6-1 and SB1-G-179-P1 are the same chemical compound and have identical chemical structures. This information does not serve to overcome the prima facie case of obviousness.
MAINTAINED/MODIFIED REJECTIONS
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2, 14, 45, 59, 64, 74, and 82-84 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Bradner et al. (USPN 10,849,980 B2)(“Bradner”) in view of Ishikawa et al. (US PG-PUB 2019/0255056 A1) (“Ishikawa”), Ishikawa et al (USPN 9,604,988 B2)(“Ishikawa No.2”), Burchat et al. (Burchat et al. "Pyrazolo [3, 4-d] pyrimidines containing an extended 3-substituent as potent inhibitors of Lck—a selectivity insight." Bioorganic & Medicinal Chemistry Letters 12, no. 12 (2002): 1687-1690) (“Burchat”), Calderwood, D.J., Johnston, D.N., Munschauer, R. and Rafferty, P., 2002. Pyrrolo [2, 3-d] pyrimidines containing diverse N-7 substituents as potent inhibitors of Lck. Bioorganic & Medicinal Chemistry Letters, 12(12), pp.1683-1686. (“Calderwood”), Sabat et al (Sabat, M., VanRens, J.C., Laufersweiler, M.J., Brugel, T.A., Maier, J., Golebiowski, A., De, B., Easwaran, V., Hsieh, L.C., Walter, R.L. and Mekel, M.J., 2006. The development of 2-benzimidazole substituted pyrimidine based inhibitors of lymphocyte specific kinase (Lck). Bioorganic & medicinal chemistry letters, 16(23), pp.5973-5977)(“Sabat”) and Watkins (US PG-PUB 2007/0281907 A1)(“Watkins”)
Regarding claim 1, Bradner teaches bifunctional compounds similar to the instant application that are “bifunctional compounds which act as protein degradation inducing moieties” (Abstract), also known in the art as PROTACs consisting of a targeting ligand, linker and degron.
Bradner also teaches bifunctional compounds of Formula X, I-11 that are comprised of (column 3, lines 25-50): a) an E3 Ubiquitin Ligase binding moiety aka a Degron (column 2, lines 18-23), b) a linker, which “is a group that covalently binds to the Targeting ligand” (column 2, lines 18-23), and c) a targeting ligand….which “is a small molecule which is capable of binding to or binds to a target protein of interest” (column 3, lines 50-56),” where the target protein can be a kinase such as “a kinase to which the Targeting Ligand is capable of binding or binds includes, but is not limited to, a tyrosine kinase (e.g., HCK)” (column 48, lines 37-45).
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Consequently, Bradner teaches the key functional components required to build a PROTAC that can be simply modified in a highly modular fashion based on the target protein through substituting the targeting ligand for an inhibitor selective for the protein of interest and specifically identifies target proteins that would be suitable for such experimentation (i.e..: HCK).
Bradner teaches the linkers that meet the limitations recited in instant claims 1, 74 and 82 as exemplified by dBET18 shown below (column 203-204, top molecule).
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Bradner additionally teaches that the linker between the degron and targeting ligand can be of Formula L1 or L2, where TL is the targeting ligand; W is independently absent, CH, O, S, NH or NR5; Z is absent, CH, O, NH or NR5 (column 37-39).
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Bradner also teaches linkers such as:
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Consequently, Bradner’s teachings meet the limitation of claims 74 and 82 shown below:
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Regarding selecting a linker, Bradner further teaches that “The Linker is a bond or a carbon chain that serves to link a Targeting Ligand with a Degron (column 37, lines 41-42).
Bradner further teaches preferred embodiments using PEGylated linkers “the Linker may be a polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units (column 47, 30-36),” as used in elected species SB1-G-185.
Bradner further provides guidance for optimizing the linker, specifically that “In certain embodiments, the Linker is designed and optimized based on SAR (structure-activity relationship) and X-ray crystallography of the Targeting Ligand with regard to the location of attachment for the Linker.
In certain embodiments, the optimal Linker length and composition vary by target and can be estimated based upon X-ray structures of the original Targeting Ligand bound to its target. Linker length and composition can be also modified to modulate metabolic stability and pharmacokinetic (PK) and pharmacodynamics (PD) parameters.
In certain embodiments, where the Target Ligand binds multiple targets, selectivity may be achieved by varying Linker length where the ligand binds some of its targets in different binding pockets, e.g., deeper or shallower binding pockets than others (column 37,lines 36-51).”
Consequently, Bradner provides specific guidance for ranges of linker lengths specifically using ethylene glycol units and how to optimize the linker length to achieve the desired pharmacological profile and compound properties.
Bradner also teaches where D is an E3 ubiquitin binding moiety as recited in instant claim 1 and the degron recited in claim 45 (column 16-37).
By example only, Compound dBEt18 of Bradner incorporates one degron recited in instant claim 45 (column 203-204, top molecule, shown below).
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Bradner teaches other working examples for bifunctional compounds employing ethylene glycol linkers with the degron (column 45-46, bottom of page).
Bradner does not explicitly teach the targeting ligands and/or compounds disclosed in the instant application or Claim 83 including the elected species.
Regarding Claims 1-2, 14, 59, 64, 83-84 Ishikawa teaches pyrrolopyrimidine and pyrazolopyrimidine-based HCK inhibitors for treating leukemia that meet the claim limitations for the instant targeting ligand (by example only, page 8, paragraph [0099], RK-20449 (Chem 1) and page 23, paragraph [0224], Chem. 63 (RK-20620)), including the identical targeting ligand using by Applicant in SB1-G-185 from instant claim 83 (i.e.: compound 63).
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Ishikawa does not teach the aforementioned components of the PROTAC or explicitly disclose the compounds in the instant application.
Ishikawa No. 2 teaches the identical compounds to Ishikawa and additionally provides synthesis of Ishikawa’s compounds (column 21, lines 56-67, Example 1 and column 84, lines 36-56), pharmacological and biological activity (i.e.: in vitro and in vivo data, Fig. 1-5 of Ishikawa, and additionally, column 23, lines 21 for Example 1 and column 85, line 19 for Example 59), and pharmaceutical compositions for treating leukemia (abstract).
Example 1 of Ishikawa No. 2 is identical to Ishikawa’s compound 1(shown above), and identical to the targeting ligand in instant invention (i.e.: page 47 of Applicant’s specification, Compound A419250), and Example 59 of Ishikawa No. 2 is identical to Ishikawa’s compound 63, and the targeting ligand used in instant elected species SB1-G-185 (i.e.: page 48 of Applicant’s specification, compound SB1-G-112). As aforementioned, Ishikawa establishes via experimental data these compounds are HCK inhibitors with anti-cancer properties.
Calderwood also teaches the identical targeting ligand that meets the claim limitations for the instant targeting ligand (Compound A419250).
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Calderwood teaches that “Lck, an src family tyrosine kinase expressed primarily in T lymphocytes, provides a critical function during the initial steps of T-cell receptor (TCR) signaling.” The structural similarities and relationship between LCK and HCK as members of the Src kinase family were well-known in the art at the effective time of filing. It also is well-known in the art that LCK and HCK have close catalytic site homology.
By example only, Sabat teaches developing inhibitors for LCK, using X-ray co-crystallography of HCK as a strategy to determine binding modes for the LCK inhibitors, supporting the relationship and similarities between HCK and LCK.
Additionally, on page 49, paragraph [00101] of Applicant’s specification, Applicant explains that “The bifunctional compounds described herein interact with a kinase, e.g., HCK, BTK, FYN, SRC, BLK, LCK, CSK, ABL1, ABL2, LIMK1, LATS1) and an E3 ubiquitin ligase (e.g., Cereblon).” Consequently, Applicant does not specify that HCK needs to necessarily be the target of interest.
Calderwood specifically teaches SAR studies and the importance of optimizing the N-7 position (page 1684, Table 2), specifically that “We realized that a carbocyclic framework directly attached to N-7 was a motif that was beneficial for lck activity and therefore elected to append ‘solubilizing substituents’ to this motif (page 1684, column 2, last paragraph).” Calderwood additionally demonstrates beneficial pharmacokinetic properties for N-7 substituent (page 1685, column 1, Table 4 and paragraphs 1-2).
Burchat also teaches the identical targeting ligand (compound SB1-G-112) that meets the claim limitations for the instant targeting ligand for the elected species SB1-G-185 (shown below) and specifically teaches the importance of the para-phenoxyphenyl moiety.
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Burchat teaches “The para-phenoxyphenyl analogue 2 is an orally active lck inhibitor with a bioavailability of 69% and exhibits an extended duration of action in animal models of T cell inhibition.”
Burchat also teaches SAR studies resulting in compound 2, particularly that “In summary, the nature of the Ph-X-Ph linker in these tyrosine kinase inhibitors defines the potency and, perhaps more interestingly, the selectivity for lck, src, kdr and tie-2…. In line with its lower LogD compared to compound 1, the ether-linked pyrazolopyrimidine 2 exhibits an enhanced pharmacokinetic profile and also portrays prolonged activity in animal models of T cell activation after oral administration.”
Finally, Watkins teaches “phosphorus substituted kinase inhibitory conjugates, compositions containing such conjugates, and therapeutic methods that include the administration of such conjugates, as well as to processes and intermediates useful for preparing such conjugates(abstract).”
Watkins more specifically teaches the identical targeting ligand to instant invention can be used to make conjugates for anti-cancer applications (claim 4 of Watkins, compound IVa, which is instant compound SB1-G-112).
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Watkins teaches on page 26, paragraph [0287] that “The invention provides conjugates that comprise a kinase inhibiting compound that is linked to one or more phosphonate groups either directly (e.g. through a covalent bond) or through a linking group (i.e. a linker).”
At page 6, paragraph [0081], Watkins additionally teaches that “The kinase inhibitory compounds provided herein, which meet such needs, may be used to treat breast cancer, non-small cell lung cancers (NSCLCs), adenocarcinomas, squamous cell cancer of the lung, oesophageal cancer, gastrointestinal cancer, colon cancer, rectal cancer, stomach cancer, prostate cancer, leukaemia, ovarian cancer, bronchial cancer, pancreatic cancer, thyroid cancer, uterine cancer, brain cancer, lung squamous cell cancer, bladder cancer, gastric cancer, head and neck cancer, gynaecological and thyroid tumors, to prevent the development of resistance (multi-drug resistance) in cancer treatment with other chemotherapeutic drugs or remove existing resistance to other chemotherapeutic drugs, retinopathies, hemangioblastoma, hemangioma, and neoplastic diseases, gliomas, to inhibit tumor angiogenesis, myelomas, chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), inoperable and/or metastatic malignant gastrointestinal stromal tumors (GISTs), treatment of inflammatory diseases such as rheumatoid arthritis, Crohn's disease, treatment of cell proliferation diseases, and for the treatment of transplant rejection and psoriasis.”
Watkins does not teach the identical conjugate as instant invention (i.e.: PROTACs).
The specific components taught by Bradner and Ishikawa are shown below using SB1-G-185 from instant claim 83 as elected by Applicant for species election, in addition to the conceptual framework established by Bradner for PROTACs as aforementioned.
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A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990) (discussed below and in MPEP § 2144) for an extensive review of the case law pertaining to obviousness based on close structural similarity of chemical compounds. See also MPEP § 2144.08, subsection II.A.4.(c). See MPEP § 2144.09.
Therefore, it would have been prima facie obvious for an ordinarily skilled-artisan in the field of medicinal chemistry before the effective filing date of the claimed invention to have combined the teachings of Bradner, Ishikawa, Burchat, Calderwood and Watkins to develop a bifunctional compound known as a PROTAC to target kinases including HCK because Bradner teaches the framework for making a bifunctional molecule for protein degradation (i.e..: PROTAC) consisting of a degron, linker and targeting ligand, applications in cancer therapeutics, that kinases such as HCK are suitable to target, the identical degrons, and the identical linker and because Ishikawa, Burchat, Calderwood and Watkins teach specific pyrrolopyrimidine and pyrazolopyrimidine compounds that are identical to instant targeting ligands for treating leukemia that are HCK/LCK inhibitors. Burchat and Calderwood additionally teach SAR studies for the instant targeting ligands, and Watkins teaches that the identical kinase inhibitors can be used to make conjugates. Bradner additionally teaches methods for optimization of the linker length and other key parameters in PROTAC design.
A person of ordinary skill in the art would have been motivated to modify the invention of Bradner to incorporate the HCK targeting ligands taught by Ishikawa, Burchat, Calderwood and Watkins to develop PROTACs targeting kinases such as HCK for cancer treatment because Bradner teaches kinases such as HCK are suitable protein targets and it is known in the art that PROTACs offer unique advantages over conventional therapeutics including potential to control degradation of undruggable proteins, bypass toxic effects, improved specificity and need for low concentrations, because Watkins additionally teaches that identical compounds are suitable conjugation chemistry and because Ishikawa, Burchat, and Calderwood teach compounds with anti-cancer properties directed towards identical protein targets.
Therefore, an ordinarily-skilled artisan in the field of medicinal chemistry would have arrived at the structures of the instantly claimed invention as a predictable result with a reasonable expectation of success. PROTACs are known to be modular in design as further taught by Bradner; therefore, simply substituting the targeting ligand for the HCK inhibitors taught by Ishikawa, Burchat, Calderwood and Watkins and applying routine optimization through standard structure-activity relationship (SAR) studies as commonly done in the art and based on the guidance provided by Bradner for optimization and what was known in the art as of the effective filing date of the claimed invention would provide the claimed invention as a predictable result with a reasonable expectation of success based on the beneficial teachings of Bradner, Ishikawa, Burchat, Calderwood and Watkins.
It would have been further prima facie obvious to obtain the instantly claimed compositions using the compounds in instant claim 1 since the compositions recited in claim 84 are highly predicable results that would have reasonable expectation of success based on the teachings of Bradner, Ishikawa, Burchat, Calderwood and Watkins and what is known in the prior art for formulation of pharmaceutical compositions.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1-2, 14, 45, 59, 64, 74, 82, and 83 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/033,872 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets recite identical bifunctional compounds for targeting protein degradation of kinases.
Claim 1 of ‘872 recites compound SB1-G-200 as an alternative which is also encompassed by instant claims 1-2, 14, 45, 59, 64, 67, 74, and 82 and explicitly claimed in instant claim 83 (shown below, see page 27 of instant claims).
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Therefore, claim 1 of ‘872 clearly anticipates instant claims 1-2, 14, 45, 59, 64, 74, 82, and 83.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The Remarks of September 8, 2025 have been fully considered but are not fully persuasive for the reasons below. The Examiner notes that arguments from Office Actions dated December 31, 2024; July 14, 2025 and November 5, 2025 are additionally incorporated by reference herein.
35 USC § 103
Applicant’s Argument:
“Applicant respectfully traverses. The rejection does not establish a sustainable case of prima facie obviousness, considered from the standpoint of any of the tests enunciated by the Supreme Court in KSR (KSR Int 'l Co. V. Teleflex Inc., 550 U.S. 398 (2007)). Nor does the rejection establish a sustainable case of prima facie obviousness, considered from the standpoint of the body of Federal Circuit decision authority known as "lead compound analysis (LCA)."
Examiner’s Response:
The Examiner appreciates Applicant’s arguments; however, respectively disagrees for the reasons stated in previous office actions pertaining to “lead compound analysis.”
For the purposes of clarity for the record, the Examiner restates arguments provided in the Final Rejection dated July 14, 2025, with modifications to include Watkins, Calderwood and Burchat.
The main premise from Applicant is that Bradner fails as a primary reference for not teaching a “lead” compound. The examiner disagrees with Applicant’s assertions on requirement for a “lead” compound for obviousness and what can constitute a “lead” compound.
As per MPEP 2143.B, example 9, “The Federal Circuit in Eisai makes it clear that from the perspective of the law of obviousness, any known compound might possibly serve as a lead compound: "Obviousness based on structural similarity thus can be proved by identification of some motivation that would have led one of ordinary skill in the art to select and then modify a known compound (i.e. a lead compound) in a particular way to achieve the claimed compound." Eisai, 533 F.3d at 1357, 87 USPQ2d at 1455.”
As aforementioned, Bradner, Ishikawa, Burchat, Calderwood and Watkins’s inventions share structural and functional similarities with instant invention.
Additionally, “It should be noted that the lead compound cases do not stand for the proposition that identification of a single lead compound is necessary in every obviousness rejection of a chemical compound. For example, one might envision a suggestion in the prior art to formulate a compound having certain structurally defined moieties, or moieties with certain properties. If a person of ordinary skill would have known how to synthesize such a compound, and the structural and/or functional result could reasonably have been predicted, then a prima facie case of obviousness of the claimed chemical compound might exist even without identification of a particular lead compound. As a second example, it could be possible to view a claimed compound as consisting of two known compounds attached via a chemical linker. The claimed compound might properly be found to have been obvious if there would have been a reason to link the two, if one of ordinary skill would have known how to do so, and if the resulting compound would have been the predictable result of the linkage procedure. Thus, Office personnel should recognize that in certain situations, it may be proper to reject a claimed chemical compound as obvious even without identifying a single lead compound.” See MPEP 2143.B, example 10.
The second example regarding attaching two known compounds via a chemical linker aptly applies to the current invention pertaining to combining Bradner, Ishikawa, Burchat, Calderwood and Watkins.
Bradner teaches the framework for the PROTAC consisting of a degron, linker, and targeting ligand and that HCK is a suitable target protein. Ishikawa teaches a library of compounds capable of binding HCK.
The examiner has provided a reasonable rationale for why a person of ordinary skill in the art would have been motivated to make such a substitution and Bradner has indicated that the targeting ligand is primed to be substituted specifically for a compound that can bind a HCK kinase (i.e.: an inhibitor). Bradner provides motivation to link both compounds as a predictable result that a person of ordinary skill in the art would know how to make with a reasonable expectation of success. Consequently, it is proper to reject the instantly claimed invention as obvious on this basis.
As aforementioned, the degron is well-known in the art and taught by Bradner and Ishikawa teaches HCK inhibitors, including the one identical to the elected species. The Examiner has provided further evidence from Ishikawa, Calderwood, Burchat, and Watkins who also teach the identical inhibitors used as targeting ligands in instant invention, and further details regarding biological activity and SAR studies employed in molecule development, all which support that the inhibitors demonstrate anti-cancer properties. Watkins additionally teaches that such inhibitors can be used to make conjugates. All evidence was previously suggested to Applicant as relevant prior art.
Bradner has provided the framework and motivation for the degron and targeting ligand to be linked (i.e.: to access PROTACs targeting HCK). The examiner has provided reasonable rationale for why a person of ordinary skill in the art would be motivated to make such a substitution and Bradner has indicated that the targeting ligand is primed to be substituted specifically for a compound that can bind HCK (i.e.: an inhibitor). Bradner has also provided the motivation in developing new therapeutics for cancer.
Consequently, the examiner has provided a proper prima facie case for obviousness based on what was known at the time for PROTACs. That is, a person of ordinary skill in the art would have been motivated to combine the teachings of Bradner with the inhibitors described by Ishikawa, Calderwood, Burchat, and Watkins to access PROTACs targeting HCK. Additionally, the artisan would have had a reasonable expectation of success in accessing such compounds as a predictable result through routine optimization as part of the drug discovery process common to the field of medicinal chemistry. It is not unexpected that the resulting compounds would demonstrate anti-cancer properties based on the beneficial teachings of Bradner, Ishikawa, Calderwood, Burchat, and Watkins.
Applicant’s Argument:
“Ironically, while the Office has pointed to Bradner (which was first filed in late 2014-early 2015) as providing a "framework" and the "key functional components," the art's process of providing "foundations" for PROTAC design remains ongoing more than a decade later. That aside, the Office has embellished Bradner (which as argued previously and reiterated below), does not even disclose a targeting ligand that binds HCK, which is most certainly a "key component" of the claimed compounds.”
Examiner’s Response:
The examiner respectfully disagrees, and has already provided extensive support from not only Brader for the framework, but additionally Ishikawa, Calderwood, Burchat, and Watkins.
Again, Applicant is reminded that in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012). Please see MPEP 2145.IV for further guidance.
Applicant’s Argument:
Second, the state of the art does not support the notion that substituting Ishikawa's, Burchat's, Calderwood's, and Watkins's HCK inhibitors for Bradner's targeting ligand would have "obtained" a "predictable" result, i.e., degradation of HCK. Bradner does not demonstrate degradation of HCK. For that matter, it does not disclose a bifunctional compound that degrades HCK or even a single targeting ligand that binds HCK. Bradner focuses on different targets, namely BRD2, BRD3, BRD4, FKBP12, and GR, and shows degradation of those targets. At best, it lists HCK in a laundry list of potentials targets. See, Bradner at column 48. An experimental demonstration of degradation of one or a couple of kinases does not provide a reasonable expectation of success regarding other kinases.
Examiner’s Response:
Once more, Applicant is reminded that in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012). Please see MPEP 2145.IV for further guidance.
Applicant is also reminded that as per MPEP 2121: “A prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation." Impax Labs. Inc. v. Aventis Pharm. Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006) (citing Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1326, 75 USPQ2d 1297, 1302 (Fed. Cir. 2005)).\
As previously explained in prior Office Actions, Applicant’s arguments are singularly focused on predictability for the PROTACs to actually degrade the targeting protein HCK, not whether the PROTACs would be predictable to make and access. As noted, Applicant’s own specification is not specific that the targeting protein needs to be HCK or that degradation is a required feature.
On page 2, paragraph [0004], Applicant explains “Described herein are bifunctional compounds of Formula (I). The compounds described herein include a component that binds to the target kinase (e.g., HCK, BTK, FYN, SRC, BLK, LCK, CSK, ABL1, ABL2, LIMK1, LATS1) and a component that binds an E3 ubiquitin ligase (e.g., lenalidomide, thalidomide) and therefore may be useful in promoting and/or inducing the degradation of a kinase (e.g., HCK, BTK, FYN, SRC, BLK, LCK, CSK, ABLI, ABL2, LIMK1, LATS1)… The compounds may be useful in treating and/or preventing diseases and conditions, such as a proliferative disease associated with a target kinase (e.g., HCK, BTK, FYN, SRC, BLK, LCK, CSK, ABL1, ABL2, LIMK1, LATS1)… The compounds may be useful in treating and/or preventing diseases and conditions, such as a proliferative disease associated with HCK.”
Applicant is reminded as per MPEP 211: “During patent examination, the pending claims must be "given their broadest reasonable interpretation consistent with the specification."
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “degradation of HCK”) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Once more, Applicant’s claims are directed towards a compound of Formula (I).
The Examiner has additionally demonstrated that Applicant’s own specification is broad and describes properties for the bifunctional compounds claims, “may be useful in promoting and/or inducing the degradation of a kinase,” and “may be useful in treating and/or preventing diseases and conditions such as a proliferative disease associated with a target kinase.”
Applicant’s Argument:
The Office gives passing regard with respect to the properties of a claimed compound (page 26). Yet, in others, it clearly suggests (pages 24-25) that since claims "must be given their broadest reasonable interpretation during patent examination," and that the specification is "broader" than the claims, and the claims do not explicitly recite that the compounds "degrades HCK," the obviousness determination distills to the question of whether it would have just been obvious to "access", i.e., make, the compounds regardless of whether a person of ordinary skill in the art reasonably expected them to degrade HCK. This position is legally unfounded. First, the obviousness determination must be based on the claims, not on the specification. Second, a claimed compound and all its properties are considered inseparable. See, MPEP § 2141.02 (V) "DISCLOSED INHERENT PROPERTIES ARE PART OF 'AS A WHOLE' INQUIRY (See also In re Papesch, 315 F.2d 381, 391, 137 USPQ 43, 51 (CCPA 1963) ("From the standpoint of patent law, a compound and all its properties are inseparable.")). Third, the claims need not explicitly recite how the compound works or the results it achieves. Fourth, the prior art must provide not only "a motivation to make" but a reasonable expectation of success with respect to the utility of the compound, as well. See, e.g., MPEP § 2143(I)(B)(citing In re Vaeck, 947 F. 2d 488, 494 (Fed. Cir. 991)(Expectation of success must be founded in the prior art, not in the applicant's disclosure.")
Examiner’s Response:
The examiner respectfully disagrees.
Applicant is invited to consult MPEP 2141. II. A, which states “In determining the scope and content of the prior art, Office personnel must first obtain a thorough understanding of the invention disclosed and claimed in the application under examination by reading the specification, including the claims, to understand what has been invented. See MPEP § 904. The scope of the claimed invention must be clearly determined by giving the claims the "broadest reasonable interpretation consistent with the specification." See Phillips v. AWH Corp., 415 F.3d 1303, 1316, 75 USPQ2d 1321, 1329 (Fed. Cir. 2005).”
Therefore, Applicant’s statements are not accurate in this regard.
Additionally, the Examiner has provided support regarding properties which is reiterated below.
As discussed previously, and by example only, Figure 1A and 1B show ED50 data for the A419259 degrader series and SB1-G-112 degrader series against the inhibitor A419259 and SB1-G-112. It is clear that excepting one compound, all compounds to show activity against the cancer cell lines tested. In many instances, the inhibitors themselves show superior results compared to the actual PROTAC analogues made. It is not unexpected that the instant invention’s compounds would have anti-cancer properties based on the prior art and what was known about A419259. Additionally, based on comparative ED50 data alone, Applicant fails to show that the PROTACs claimed are significantly more potent compared to inhibitors alone. Consequently, such results cannot be taken as unexpected.
As aforementioned, similar arguments by Applicant were previously presented and the Examiner has incorporated their responses by reference.
The Examiner reiterates their previous remarks, particularly, that they have provided detailed analysis to set forth a reasonable prima facie case of obviousness as per MPEP 2143 in this Office Action and previous Office Actions.
As previously mentioned, Applicant has failed to provide support suggesting synthesizing the compounds claims would be an insurmountable challenge and additionally, limitations from the specification are not read into the claims; therefore, the compounds are not required to achieve degradation of HCK.
As per MPEP 716.02 (c): Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978)
Additionally, as per MPEP 716.02: “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Consequently, the burden once more shifts to Applicant to provide additional evidence and/or support of nonobviousness and unexpected results.
Applicant is further reminded that arguments do not take the place of evidence on the record and the burden is on Applicant to demonstrate that such results are truly unexpected.
The examiner appreciates Applicant’s remarks; however, for the reasons set forth, they are not fully persuasive.
Double Patenting
The double patenting rejection over co-pending Application No. 18/033,872 is maintained and Applicant has provided no arguments at this point traversing the rejection.
Conclusion
Claims 1-2, 14, 45, 59, 64, 74, and 82-84 are currently pending and remain rejected.
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN L. LADD whose telephone number is (703)756-5313. The examiner can normally be reached M-Th, 7:00 am to 5:30 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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